Core E: Biomarker PROJECT SUMMARY/ABSTRACT Alzheimer disease (AD) will become a public health crisis in the very near future if left untreated. There are currently no proven treatments that delay the onset or prevent the progression of AD, although several promising candidates are being tested. During therapy development, it will be critical to have biomarkers that identify individuals at high risk for AD in order to target them for clinical trials and to monitor therapy. Autosomal-dominant AD (ADAD) accounts for a very small proportion of all AD cases (<1%) but the neuropathologic hallmarks and clinical features are similar to the more common sporadic, late-onset form (LOAD). Individuals possessing AD mutations are destined to develop the disease and at a relatively predictable age, thus providing a unique cohort in which to investigate the trajectories/timing of underlying AD pathologies, especially as one transitions from the preclinical/asymptomatic to the symptomatic stage. During the initial funding periods of DIAN, the Biomarker Core analyzed CSF and plasma samples obtained from participants at baseline, including mutation carriers (MC) and non-carriers (NC) that fell along a wide spectrum of estimated years to symptom onset (EYO). Cross-sectional analyses demonstrated elevated CSF tau and ptau181, markers of neuronal injury and/or neurofibrillary tangles, ~10-20 years prior to the estimated age of symptom onset (EYO -10 to -20). Low levels of CSF A?1-42, a marker of ?-amyloid plaques, were first observed in MC at ~EYO -10, but levels appeared to start to decline much earlier (~EYO -25) from levels initially higher than NC. Interestingly, more recent analyses of longitudinal samples revealed a slowing of the increase in CSF tTau and an actual reduction in pTau levels in symptomatic MC (EYO>0) over time, perhaps reflecting its sequestration into tangles in the brain as is observed for CSF A?1-42 during the development of plaques. These results emphasize the importance of longitudinal, within-person assessment when modeling biomarker trajectories across the natural course of the disease. What remains to be determined is the trajectory of biomarker changes within MC as they progress from the asymptomatic to the symptomatic stages. Such information will be critical for the design and evaluation of clinical trials intended to prevent the onset of cognitive decline in individuals at risk for developing dementia due to AD. In the present application, we will build upon our success through four Specific Aims: Aim 1) Maintain and grow the biorepository of DIAN CSF and plasma samples and coordinate the distribution of samples to qualified investigators for approved scientific studies; Aim 2) Obtain measures of established biomarker analytes in CSF (A?1-40, A?1-42, t-Tau, p-Tau181) using the next generation, high-performance Lumipulse automated assay platform in order to support the aims of the DIAN cores and projects; Aim 3) Maintain 21 C.F.R. 11 compliance for all Biomarker Core functions involving electronic data; and Aim 4) Perform quality control evaluation of CSF biomarker assay rigor (precision and accuracy) and reproducibility.